Congenital Sensorineural Deafness in Australian Stumpy-Tail Cattle Dogs Is an Autosomal Recessive Trait That Maps to CFA10

Congenital sensorineural deafness is an inherited condition found in many dog breeds, including Australian Stumpy-tail Cattle Dogs (ASCD). This deafness is evident in young pups and may affect one ear (unilateral) or both ears (bilateral). The genetic locus/loci involved is unknown for all dog breeds. The aims of this study were to determine incidence, inheritance mechanism, and possible association of congenital sensorineural deafness with coat colour in ASCD and to identify the genetic locus underpinning this disease.A total of 315 ASCD were tested for sensorineural deafness using the brain stem auditory evoked response (BAER) test. Disease penetrance was estimated directly, using the ratio of unilaterally to bilaterally deaf dogs, and segregation analysis was performed using Mendel. A complete genome screen was undertaken using 325 microsatellites spread throughout the genome, on a pedigree of 50 BAER tested ASCD in which deafness was segregating. Fifty-six dogs (17.8%) were deaf, with 17 bilaterally and 39 unilaterally deaf. Unilaterally deaf dogs showed no significant left/right bias (p = 0.19) and no significant difference was observed in frequencies between the sexes (p = 0.18). Penetrance of deafness was estimated as 0.72. Testing the association of red/blue coat colour and deafness without accounting for pedigree structure showed that red dogs were 1.8 times more likely to be deaf (p = 0.045). The within family association between red/blue coat colour and deafness was strongly significant (p = 0.00036), with red coat colour segregating more frequently with deafness (COR = 0.48). The relationship between deafness and coat speckling approached significance (p = 0.07), with the lack of statistical significance possibly due to only four families co-segregating for both deafness and speckling. The deafness phenotype was mapped to CFA10 (maximum linkage peak on CFA10 -log10 p-value = 3.64), as was both coat colour and speckling. Fine mapping was then performed on 45 of these 50 dogs and a further 48 dogs (n = 93). Sequencing candidate gene Sox10 in 6 hearing ASCD, 2 unilaterally deaf ASCD and 2 bilaterally deaf ASCD did not reveal any disease-associated mutations.Deafness in ASCD is an incompletely penetrant autosomal recessive inherited disease that maps to CFA10

A mathematical and computational review of Hartree-Fock SCF methods in Quantum Chemistry

We present here a review of the fundamental topics of Hartree-Fock theory in Quantum Chemistry. From the molecular Hamiltonian, using and discussing the Born-Oppenheimer approximation, we arrive to the Hartree and Hartree-Fock equations for the electronic problem. Special emphasis is placed in the most relevant mathematical aspects of the theoretical derivation of the final equations, as well as in the results regarding the existence and uniqueness of their solutions. All Hartree-Fock versions with different spin restrictions are systematically extracted from the general case, thus providing a unifying framework. Then, the discretization of the one-electron orbitals space is reviewed and the Roothaan-Hall formalism introduced. This leads to a exposition of the basic underlying concepts related to the construction and selection of Gaussian basis sets, focusing in algorithmic efficiency issues. Finally, we close the review with a section in which the most relevant modern developments (specially those related to the design of linear-scaling methods) are commented and linked to the issues discussed. The whole work is intentionally introductory and rather self-contained, so that it may be useful for non experts that aim to use quantum chemical methods in interdisciplinary applications. Moreover, much material that is found scattered in the literature has been put together here to facilitate comprehension and to serve as a handy reference.Comment: 64 pages, 3 figures, tMPH2e.cls style file, doublesp, mathbbol and subeqn package

Approach to canine paroxysmal dyskinesias

The term ‘paroxysmal dyskinesia’ (PD) describes a manifestation of involuntary movement or muscle tone, which by definition is episodic in nature and self-limiting. The PDs remain poorly understood and frequently under-recognised conditions in veterinary patients. The purpose of this article is to review the basic classification and principles of recognition and diagnosis of PDs. This article introduces some of the breed-specific PDs, as well as the treatment/management options available and expected outcomes

Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors

Background: Intervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/Principal Findings: We have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-gamma, IL-2, TNF-alpha production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8+ T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.Conclusions: Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption

Problem drug use the public health imperative: what some of the literature says

<p>Abstract</p> <p>Background</p> <p>With more than 200,000 problem drug users is contact with structured treatment services in England the public health imperative behind drug treatment is great. Problem drug use for many is a chronic and relapsing condition, where "cure" is often neither a reasonable or appropriate expectation and it can further be argued that in these circumstances problem drug use is no different from any number of chronic and enduring health conditions that are managed in the health care system and therefore should be conceptualised as such.</p> <p>Discussion</p> <p>A public health approach to drug treatment emphasises the need for drug users in or accessing treatment, to reduce their harmful drug use, reduce drug use related risks such as sepsis and overdose and stay alive for longer. However a public health perspective in relation to problem drug use isn't always either apparent or readily understood and to that end there is still a significant need to continue the arguments and debate that treatment and interventions for problem and dependent drug users need to extend beyond an individualistic approach. For the purposes of discussion in this article public and population health will be used interchangeably.</p> <p>Summary</p> <p>A recognition and acceptance that a public and population health approach to the management of problem drug users is sound public health policy also then requires a long term commitment in terms of staffing and resources where service delivery mirrors that of chronic condition management.</p

Gravitational Wave Detection by Interferometry (Ground and Space)

Significant progress has been made in recent years on the development of gravitational wave detectors. Sources such as coalescing compact binary systems, neutron stars in low-mass X-ray binaries, stellar collapses and pulsars are all possible candidates for detection. The most promising design of gravitational wave detector uses test masses a long distance apart and freely suspended as pendulums on Earth or in drag-free craft in space. The main theme of this review is a discussion of the mechanical and optical principles used in the various long baseline systems in operation around the world - LIGO (USA), Virgo (Italy/France), TAMA300 and LCGT (Japan), and GEO600 (Germany/U.K.) - and in LISA, a proposed space-borne interferometer. A review of recent science runs from the current generation of ground-based detectors will be discussed, in addition to highlighting the astrophysical results gained thus far. Looking to the future, the major upgrades to LIGO (Advanced LIGO), Virgo (Advanced Virgo), LCGT and GEO600 (GEO-HF) will be completed over the coming years, which will create a network of detectors with significantly improved sensitivity required to detect gravitational waves. Beyond this, the concept and design of possible future "third generation" gravitational wave detectors, such as the Einstein Telescope (ET), will be discussed.Comment: Published in Living Reviews in Relativit

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.